Method for the synthesis of 3-r-1,4,2-dioxazol-5-ones technical field

ABSTRACT

Provided are methods of preparing 3-R-1,4,2-dioxazol-5-one compounds using convenient and efficient methods. Also provided are 3-R-1,4,2-dioxazol-5-one compounds produced using the methods described.

TECHNICAL FIELD

The present disclosure relates to preparation of3-R-1,4,2-dioxazol-5-one compounds. In particular, the presentdisclosure relates to a more convenient method for the preparation of3-R-1,4,2-dioxazol-5-one compounds than was previously known orutilized.

BACKGROUND

In recent years, 3-R-1,4,2-dioxazol-5-one compounds have been found tobe versatile reagents, especially for regioselective amidation at theortho C—H position of aromatic moieties. These reagents act via theformation of N-acyl nitrene intermediates and are most often used withelectron-poor aromatic substrates, such as those with ketone, aldehyde,2-phenylpyridine, nitrosoaniline, arylimidazole, 2-pyridinyl ferrocenes,and indoline substituents. They are finding increasingly diverseapplications, including the amidation of N-sulfonyl ketimines,thiadiazine-1-oxides, and thioamides. Alkenyl azoles can befunctionalized, and the Lossen rearrangement can be used to efficientlyprepare isocyanates, allowing a more environmentally-friendlyalternative for the Hoffmann and the Curtius rearrangements. Togetherwith N-azolo imines and a Rh(III) catalyst, they can be used to makeazolo[1,3,5]triazines, common motifs used in drug design, forenantioselective hydroamination of vinyl arenes with a copper hydridecatalyst, to amidate olefin or aryl C—H bonds to make enamides andpyrimidones, which can also act as a directing group for a second C—Hamidation, and for the ortho-imidation of substituted imadazopyridines.Recently, 3-methyl-1,4,2-dioxazol-5-one found a completely new use as anelectrolyte additive for improving the performance of lithium-ion cells.Even more recently, the closely related 3-phenyl-1,4,2-dixoazol-5-onewas similarly tested as an electrolyte additive and was shown tosignificantly extend the lifetime of lithium-ion cells during prolongedcycling.

To further increase the use of dioxazolone compounds, robust methods areneeded that can be used to prepare them with a wide range of functionalgroup substitutions. Historically, these compounds have been prepared bycombining a hydroxamic acid with N,N′-carbonyldiimidazole (“CDI”) indichloromethane as shown below in Reaction I.

Reaction I shows the historically used route for the synthesis of3-phenyl-1,4,2-dioxazol-5-one from benzohydroxamic acid andN,N′-carbonyldiimidazole.

Occasionally, acetonitrile or ethyl acetate has been used as the solventinstead. While this method generally provides products with highpurities and high yields, many hydroxamic acids are not commerciallyavailable, limiting the range of compounds that easily can be preparedby this route. Furthermore, many of the existing methods involve the useof dichloromethane, a relatively hazardous and environmentally harmfulsolvent that is not favored by some industrial chemical producers. Whilehydroxamic acids can be easily prepared via the reaction of acylchlorides with hydroxylamine hydrochloride in a biphasic system of waterand diethyl ether, using sodium carbonate as a base, the hydroxamicacids are often difficult to isolate from the reaction mixture, and thescope of this reaction is limited by the use of water, which means thehydroxamic acids must be thoroughly dried so as to not hydrolyze the CDIused for formation of the 1,4,2-dixoazol-5-ones.

The reaction route used to date for production of3-R-1,4,2-dioxazol-5-one compounds is time consuming, inefficient, andexpensive and there is a need for improvement to the methods forproduction of these compounds. In the present disclosure, presented is amore simplified approach to synthesizing3-aryl-substituted-1,4,2-dixoazol-5-ones using a “one-pot” method thatemploys inexpensive, commercially available aryl acyl chlorides,hydroxylamine hydrochloride, and CDI. The reaction proceeds readilyunder mild conditions and requires no expensive catalysts to proceed.

SUMMARY

According to certain embodiments, provided is a method of preparing3-R-1,4,2-dioxazol-5-one compounds. The method includes the steps of:combining hydroxylamine hydrochloride, triethylamine, and a firstorganic solvent to prepare a reaction mixture; dissolving aR-substituted acyl chloride in a second organic solvent to prepare aR-substituted acyl chloride solution; dissolving triethylamine in athird organic solvent to prepare a triethylamine solution; adding theR-substituted acyl chloride solution and the triethylamine solution tothe reaction mixture over a first predetermined time period; stirringthe resulting reaction mixture for a second predetermined amount oftime; adding CDI to the reaction mixture; stirring the resultingreaction mixture for a third predetermined amount of time; adding acidto quench the reaction; and obtaining a 3-R-1,4,2-dioxazol-5-onecompound. In some embodiments, the R-substituted acyl chloride isselected from benzoyl chloride, 2-thiophenecarbonyl chloride, p-toluoylchloride, 2-naphthoyl chloride, p-fluorobenzoyl chloride,m-fluorobenzoyl chloride, o-fluorobenzoyl chloride, p-methoxybenzoylchloride, p-nitrobenzoyl chloride, m-nitrobenzoyl chloride,o-nitrobenzoyl chloride, p-teraphthaloyl chloride, p-chlorobenzoylchloride, m-chlorobenzoyl chloride, or o-chlorobenzoyl chloride.

In yet further embodiments, the first organic solvent isN,N-dimethylformamide. In some embodiments, the second organic solventis ethyl acetate or tetrahydrofuran. In other embodiments, the thirdorganic solvent is ethyl acetate or tetrahydrofuran. The second andthird organic solvents may be the same or different.

In some embodiments, the first predetermined amount of time is ten ormore minutes. In yet further embodiments, the first predetermined amountof times is between about ten and thirty minutes, between about tenminutes and two hours, is about ten minutes, about twenty minutes, aboutthirty minutes, or is more than twenty minutes, or more than thirtyminutes. In other embodiments, the first predetermined amount of time isless than about two hours. In further embodiments, the secondpredetermined amount of time is one or more hours. In yet furtherembodiments, the second predetermined amount of time is about one hour,about ninety minutes, about two hours, or between about one hour and sixhours. In yet further embodiments, the second predetermined amount oftime is less than six hours. In yet further embodiments, the thirdpredetermined amount of time is twenty or more minutes. In yet furtherembodiments, the third predetermined amount of time is between abouttwenty minutes and about one hour, between about twenty minutes andabout two hours is about twenty minutes, about thirty minutes, about onehour, or about two hours. In yet further embodiments, the thirdpredetermined amount of time is less than two hours.

In yet further embodiments, the 3-R-1,4,2-dioxazol-5-one compound has apurity of at least 50%, 55%, 60%, 65%, 70%, 75%, or greater. In otherembodiments, the method further includes the step of purifying the3-R-1,4,2-dioxazol-5-one compound to a purity of at least 75%, 80%, 85%,90%, 95%, or greater.

In other embodiments of method, the method is performed at ambienttemperature and pressure. In further embodiments of the method, thereaction mixture is cooled to 0° C. before the R-substituted acylchloride solution and the triethylamine solution are added to thereaction mixture.

In yet further embodiments of the method, the 3-R-1,4,2-dioxazol-5-onecompound is selected from 3-phenyl-1,4,2-dioxazol-5-one,3-thiophene-1,4,2-dioxazol-5-one, 3-tolyl-1,4,2-dioxazol-5-one,3-(2-naphthyl)-1,4,2-dioxazol-5-one,3-(p-fluorophenyl)-1,4,2-dioxazol-5-one,3-(m-fluorophenyl)-1,4,2-dioxazol-5-one,3-(o-fluorophenyl)-1,4,2-dioxazol-5-one,3-(p-methoxyphenyl)-1,4,2-dioxazol-5-one,3-(p-nitrophenyl)-1,4,2-dioxazol-5-one,3-(m-nitrophenyl)-1,4,2-dioxazol-5-one,3-(o-nitrophenyl)-1,4,2-dioxazol-5-one,3,3′-(1,4-phenylene)-bis-1,4,2-dioxazol-5-one,3-(p-chlorophenyl)-1,4,2-dioxazol-5-one,3-(m-chlorophenyl)-1,4,2-dioxazol-5-one, or3-(o-chlorophenyl)-1,4,2-dioxazol-5-one.

According to other embodiments provided herein, provided are3-R-1,4,2-dioxazol-5-one compounds prepared by the methods describedherein. In some embodiments, the compound is selected from-phenyl-1,4,2-dioxazol-5-one, 3-thiophene-1,4,2-dioxazol-5-one,3-tolyl-1,4,2-dioxazol-5-one, 3-(2-naphthyl)-1,4,2-dioxazol-5-one,3-(p-fluorophenyl)-1,4,2-dioxazol-5-one,3-(m-fluorophenyl)-1,4,2-dioxazol-5-one,3-(o-fluorophenyl)-1,4,2-dioxazol-5-one,3-(p-methoxyphenyl)-1,4,2-dioxazol-5-one,3-(p-nitrophenyl)-1,4,2-dioxazol-5-one,3-(m-nitrophenyl)-1,4,2-dioxazol-5-one,3-(o-nitrophenyl)-1,4,2-dioxazol-5-one,3,3′-(1,4-phenylene)-bis-1,4,2-dioxazol-5-one,3-(p-chlorophenyl)-1,4,2-dioxazol-5-one,3-(m-chlorophenyl)-1,4,2-dioxazol-5-one, or3-(o-chlorophenyl)-1,4,2-dioxazol-5-one. In yet further embodiments, thecompound is 3-methyl-1,4,2-dioxazol-5-one or3-phenyl-1,4,2-dixoazol-5-one.

In yet further embodiments, the 3-R-1,4,2-dioxazol-5-one compound has apurity of at least 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, orgreater.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is the ¹H NMR (CDCl₃, 300 MHz) spectrum for3-phenyl-1,4,2-dioxazol-5-one prepared in accordance with an embodimentas described herein.

FIG. 2 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-phenyl-1,4,2-dioxazol-5-one prepared in accordance with an embodimentas described herein.

FIG. 3 is the ¹H NMR (CDCl₃, 500 MHz) spectrum for3-(2-thiophene)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 4 is the ¹³C{¹H} NMR (CDCl₃, 75 MHz) spectrum for3-(2-thiophene)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 5 is the ¹H NMR (CDCl₃, 300 MHz) spectrum for3-(p-tolyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 6 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-(p-tolyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 7 is the ¹H NMR (CDCl₃, 500 MHz) spectrum for3-(2-naphthyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 8 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-(2-naphthyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 9 is the ¹H NMR (CDCl₃, 300 MHz) spectrum for3-(p-fluorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 10 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-(p-fluorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 11 is the ¹⁹F NMR (CDCl₃, 282 MHz) spectrum for3-(p-fluorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 12 is the ¹H NMR (CDCl₃, 300 MHz) spectrum for3-(m-fluorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 13 is the ¹³C{¹H} NMR (CDCl₃, 75 MHz) spectrum for3-(m-fluorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 14 is the ¹⁹F NMR (CDCl₃, 282 MHz) spectrum for3-(m-fluorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 15 is the ¹H NMR (CDCl₃, 500 MHz) spectrum for3-(o-fluorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 16 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-(o-fluorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 17 is the ¹⁹F NMR (CDCl₃, 470 MHz) spectrum for3-(o-fluorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 18 is the ¹H NMR (CDCl₃, 500 MHz) spectrum for3-(p-methoxyphenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 19 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-(p-methoxyphenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 20 is the ¹H NMR (CDCl₃, 300 MHz) spectrum for3-(p-nitrophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 21 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-(p-nitrophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 22 is the ¹H NMR (CDCl₃, 300 MHz) spectrum for3-(m-nitrophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 23 is the ¹³C{¹H} NMR (CDCl₃, 75 MHz) spectrum for3-(m-nitrophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 24 is the ¹H NMR (CDCl₃, 500 MHz) spectrum for3-(o-nitrophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 25 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-(o-nitrophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 26 is the ¹H NMR (CDCl₃, 500 MHz) spectrum for3,3′-(1,4-phenylene)bis-1,4,2-dioxazol-5-one prepared in accordance withan embodiment as described herein.

FIG. 27 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3,3′-(1,4-phenylene)bis-1,4,2-dioxazol-5-one prepared in accordance withan embodiment as described herein.

FIG. 28 is the ¹H NMR (CDCl₃, 500 MHz) spectrum for3-(p-chlorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 29 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-(p-chlorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 30 is the ¹H NMR (CDCl₃, 300 MHz) spectrum for3-(m-chlorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 31 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-(m-chlorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 32 is the ¹H NMR (CDCl₃, 300 MHz) spectrum for3-(o-chlorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 33 is the ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum for3-(o-chlorophenyl)-1,4,2-dioxazol-5-one prepared in accordance with anembodiment as described herein.

FIG. 34 is the ATR-FTIR spectrum for 3-phenyl-1,4,2-dioxazol-5-oneprepared in accordance with an embodiment as described herein.

FIG. 35 shows the molecular structure of 3-phenyl-1,4,2-dioxazol-5-one(1), determined by single crystal X-ray diffraction (H atoms added basedon ¹H and ¹³C NMR results) prepared in accordance with an embodiment asdescribed herein.

FIG. 36 is the mass spectrum for 3-phenyl-1,4,2-dioxazol-5-one preparedin accordance with an embodiment as described herein.

DETAILED DESCRIPTION OF THE DISCLOSURE

The following description is presented to enable any person skilled inthe art to make and use the embodiments, and is provided in the contextof a particular application and its requirements. Various modificationsto the disclosed embodiments will be readily apparent to those skilledin the art, and the general principles defined herein may be applied toother embodiments and applications without departing from the spirit andscope of the present disclosure. Thus, the present inventions are notlimited to the embodiments shown, but are to be accorded the widestscope consistent with the principles and features disclosed herein.

Again, 3-R-1,4,2-dioxazol-5-ones are a class of compounds that areincreasingly finding diverse uses, including as regioselective amidationreagents and as electrolyte additives that enable long cycling lifetimesin rechargeable lithium-ion batteries. Conventional methods for theirsynthesis tend to be slow and time-consuming, requiring isolation andthorough drying of a hydroxamic acid intermediate, followed by aseparate cyclization step with CDI. Furthermore, the cyclization istypically performed in dichloromethane, an environmentally harmfulsolvent.

This disclosure provides a new “one-pot” method for the synthesis ofthese compounds. The phrase “one-pot” method means that the methodeliminates the need for isolation of the intermediate. Additionally,according to embodiments described herein, certain methods allow forproduction of 3-R-1,4,2-dioxazol-5-ones without the use of halogenatedsolvents. In embodiments described herein, the reaction is performedusing mainly environmentally benign ethyl acetate and a relatively smallamount of N,N-dimethylformamide. According to certain embodimentsdescribed herein, the reaction proceeds readily at room temperature andrequires no expensive metal catalysts to function.

A need was identified to prepare a wider range of3-R-1,4,2-dioxazol-5-one compounds for testing as lithium-ion batteryelectrolyte additives. The thiophene-substituted compound was deemedparticularly interesting, based on a number of S-containing heterocyclicadditives that were previously reported to improve battery performanceand lifetime. However, a commercial supplier of 2-thiophene hydroxamicacid could not be located and a 2-thiophenecarbonyl chloride was usedinstead to prepare 2-thiophene hydroxamic acid in-house, according toReaction II.

The hydroxamic acid was then isolated and used to synthesize3-(2-thiophene)-1,4,2-dioxazol-5-one using the conventional Reaction I,giving an overall yield of 61%.

However, this synthetic route was unsatisfactory for a few reasons: i)it generated a significant amount of halogenated solvent waste; ii) itprovided a relatively low overall yield, and iii) it was time-consumingto isolate the intermediate reagent only to immediately use it in asubsequent reaction. For these reasons, and given the increasing demandfor these compounds in a variety of chemical applications, a goal wasestablished to develop a “one-pot” method that generates and uses thehydroxamic acid intermediate without the need for isolation in theoverall method of producing 3-R-1,4,2-dioxazol-5-one compounds. Asdescribed herein, the presently described methods have surprisinglydiscovered favorable solvent combinations and reaction parameters thatprovide acceptable yields of 3-R-1,4,2-dioxazol-5-one compounds and donot require timely and inefficient intermediate reagent isolation.

EXPERIMENTS

Identification of Solvents

p-Toluoyl chloride is less expensive and more representative of othersubstituents than the thiophene-substituted acyl chloride. Therefore, amethod was developed using p-toluoyl chloride as the starting reagent,with the objective of preparing 3-(p-tolyl)-1,4,2-dioxazol-5-one, shownas (3) in Table 2.

The first challenge was identifying a solvent in which the acylchloride, the hydroxylamine hydrochloride, and the CDI are all soluble.It was determined that hydroxylamine hydrochloride is insoluble in pureDCM, THF, and EtOAc (Table 1). Therefore none of these are suitable foruse as the reaction medium in the “one-pot” methods as described herein.All three reagents may be dissolved in chloroform and, when tested, theproduct was observed by ¹H and ¹³C NMR. However, after 1 h of reflux,the reaction yield remained modest (63%) and the purity wasunsatisfactory. The need for post-synthetic purification, the relativelylow reaction yield, the use of a toxic halogenated solvent, and the useof energy intensive reflux make this route undesirable. Finally,N,N-dimethylformamide (DMF) was tested as a solvent but gave very lowreaction yield (22%).

TABLE 1 Solvent systems tested in this work and the corresponding yieldsfor the synthesis of 3-(p-tolyl)-1,4,2-dioxazol-5-one from p-toluoylchloride, hydroxylamine hydrochloride, and CDI. Ratio Solvent 1 Solvent2 (v/v) Yield Notes Dichloromethane — —  0% Hydroxylamine not soluble insolvent Tetrahydrofuran — —  0% Hydroxylamine not soluble in solventChloroform — — 63% Product very impure, chloroform refluxed for 1 h DMFDCM 1:2 39% DCM added following formation of hydroxamic acid DMF — — 22%EtOAc — —  0% Hydroxylamine not soluble in solvent EtOAC DMF 5:1 77%Deprotonation of hydroxylamine carried out in pure DMF, then EtOAc wasadded

Next, the reaction was repeated in DMF and DCM was added immediatelybefore the addition of the CDI. This was observed to nearly double thereaction yield, but it was nonetheless quite low (39%). Finally, a 1:5blend by volume of DMF and EtOAc was tested, where the hydroxylamine wasdeprotonated in pure DMF before the addition of the co-solvent. Thisgave a significantly higher yield than any of the other solvent systems(77%). Moreover, it used only a small amount of the environmentallyunfriendly DMF, while eliminating the use of halogenated solventscompletely. When the synthesis of 3-(2-thiophene)-1,4,2-dioxazol-5-onewas repeated using this solvent blend and the one-pot method, the yieldwas significantly increased, relative to the prior art two-step methoddiscussed above (76% cf. 61%).

Preparation of 3-R-1,4,2-dioxazol-5-ones from Hydroxamic Acids

Benzohydroxamic acid (21 g, 153 mmol, 1 eq) was dissolved in 600 mL ofethyl acetate, and N,N′-carbonyldiimidazole (30 g, 185 mmol, 1.2 eq) wasadded in one portion. The reaction was stirred at room temperature for30 min, then 2 M HCl (250 mL) was added. The reaction was extracted 3×with ethyl acetate (100 mL) then dried over Na₂SO₄. The solvent wasremoved under reduced pressure to afford 16.6 g of3-phenyl-1,4,2-dioxazol-5-one (shown as (1) in Table 2) as a whitecrystalline solid (66%).

One-Pot Method—Testing Scale

Reaction III: General scheme of reaction conditions used to prepare the3-R-1,4,2-dioxazol-5-ones. R=aryl.

Hydroxylamine hydrochloride (13.2 mmol, 0.90 g, 1.1 eq), was dissolvedin N,N-dimethylformamide (DMF, 20 mL) at room temperature in a 250 mLthree-necked round-bottomed flask equipped with a magnetic stir bar.Triethylamine (13.2 mmol, 1.8 mL, 1.1 eq) was added in one portion. Thesolution was stirred for 5 minutes, then ethyl acetate (70 mL) was addedto the solution, and the reaction mixture was cooled to 0° C.R-substituted acyl chloride (12.0 mmol, 1 eq) was dissolved in 20 mL ofethyl acetate and placed into an addition funnel. Triethylamine (1.8 mL,13.2 mmol, 1.1 eq) was dissolved in another 20 mL of ethyl acetate andplaced into a separate dropper funnel. Both funnels were placed onto the250 mL three necked round-bottomed flask and the contents were addeddropwise to the reaction mixture over the course of 15 minutes. Thereaction was allowed to gradually warm up to room temperature.

For the synthesis reaction involving terapthaloyl chloride, thequantities of hydroxylamine hydrochloride, triethylamine, and CDI weredoubled, to account for the presence of two acyl chloride functionalgroups. The method, including solvent volumes, was otherwise unaltered.

After stirring for an additional five hours, N,N′-carbonyldiimidazole(CDI, 12.0 mmol, 1.95 g, 1 eq) was added in one portion to the reactionmixture containing the triethylamine and the hydroxamic acid. Thereaction was allowed to proceed for another 30 minutes at roomtemperature. Solid white triethylamine hydrochloride (Et₃NHCl) wasremoved from the reaction mixture by suction filtration. The reactionsolution was then quenched with 75 mL of 1M H₂SO_(4(aq)), extracted withethyl acetate (2×45 mL), and dried over anhydrous Na₂SO₄. The ethylacetate was evaporated under reduced pressure leaving the protonatedreaction product dissolved in DMF. Leaving the solution under vacuum fora sufficient time allows the ethyl acetate to be completely removedbefore proceeding. 10% aqueous NaHCO₃ was added to the remaining liquidto precipitate the product, which was collected by suction filtration.

Testing of Various Acyl Chlorides

The one-pot synthesis was then tested with a wide variety of aromaticacyl chlorides. Starting from benzoyl chloride, the one-pot synthesisgave high yield (81%) and purity of the target compound(3-phenyl-1,4,2-dioxazol-5-one, shown as (1) in Table 2). In addition tobenzoyl chloride itself, electron-rich benzoyl chlorides, such asp-methoxybenzoyl chloride (used to prepare3-(p-methoxy)-1,4,2-dioxazol-5-one, shown as (8) in Table 2), weresuccessful. Electron-poor benzoyl chlorides, such as p-nitrobenzoylchloride (used to prepare 3-(p-nitrophenyl)-1,4,2-dioxazol-5-one, shownas (9) in Table 2), also formed product in good yield, especially whenthe nitro group was in the para position. Lower yield was observed withm-nitrobenzoyl chloride (used to prepare3-(m-nitrophenyl)-1,4,2-dioxazol-5-one, shown as (10) in Table 2).o-nitrobenzoyl chloride (used to prepare3-(o-nitrophenyl)-1,4,2-dioxazol-5-one, shown as (11) in Table 2),however, gave a poor yield, possibly because of steric interactionsbetween the dioxazolone and the nitro group. In addition to2-thiophenecarbonyl chloride, discussed above to prepare3-(2-thiophene)-1,4,2-dioxazol-5-one, shown as (2) in Table 2, thisprocedure is also able to tolerate 2-naphthoyl chloride (used to prepare3-(2-naphthyl)-1,4,2-dioxazol-5-one, shown as (4) in Table 2). Thereaction tolerated monofluorinated benzoyl chlorides (used to prepare3-(p-fluorophenyl)-1,4,2-dioxazol-5-one,3-(m-fluorophenyl)-1,4,2-dioxazol-5-one, and3-(o-fluorophenyl)-1,4,2-dioxazol-5-one, shown as (5), (6), (7),respectively, in Table 2), regardless of the substitution pattern, aswell as monochlorinated benzoyl chlorides (used to prepare3-(p-chlorophenyl)-1,4,2-dioxazol-5-one,3-(m-chlorophenyl)-1,4,2-dioxazol-5-one, and3-(o-chlorophenyl)-1,4,2-dioxazol-5-one, shown as (13), (14), (15),respectively, in Table 2), although the yields were modest for the orthoand para isomers. Interestingly, this is the reverse of the trendobserved for the benzoyl fluorides, where the ortho-fluorophenylcompound (used to prepare 3-(o-fluorophenyl)-1,4,2-dioxazol-5-one, shownas (7) in Table 2) had the greatest yield. Generally, the introductionof fluorine moieties is known to affect compound solubility. It istherefore possible that the lower yields of the para- andmeta-substituted aryl fluorides (e.g., those used to prepare3-(p-fluorophenyl)-1,4,2-dioxazol-5-one,3-(m-fluorophenyl)-1,4,2-dioxazol-5-one, respectively) are attributableto lower solubility in the ethyl acetate used for extractions. Finally,it was considered whether the reaction would tolerate a reagent withmore than one acyl chloride group. It was found that the reactiontolerates p-teraphthaloyl chloride (used to produce 3,3′-(1,4-phenylene) bis-1,4,2-dioxazol-5-one, shown as (12) in Table 2).

Nuclear Magnetic Resonance (NMR) Spectroscopy

Solution NMR spectroscopy characterized the following compounds producedaccording to the method described above. NMR spectra were recorded oneither a Bruker 300 MHz or a Bruker 500 MHz NMR spectrometer controlledby TopSpin software. Chemical shifts are reported in ppm referenced tothe residual solvent peaks (¹H NMR) or the deuterated solvent (¹³C NMR).

TABLE 2 Structures and yields of the products prepared via the one-potmethod.

1

2

3

4

5

6

7

8

9

10

11

12

13

14

15

Compound 1 was confirmed to be 3-phenyl-1,4,2-dioxazol-5-one. Theproduct was a white solid with a melting point of 63-65° C. and provideda yield of 20.3 g, 81%. The ¹H NMR (CDCl₃, 300 MHz) is shown in FIG. 1and indicates: δ=7.87 (dt, 2H, J=1.9 Hz, 8.9 Hz), 7.67 (tt, 1H, J=1.9Hz, 8.9 Hz), 7.53 (tt, 2H, J=1.9 Hz, 8.9 Hz). The ¹³C{¹H} NMR (CDCl₃,125 MHz) is shown in FIG. 2 and indicates: δ=163.7, 154.0, 133.9, 129.5,126.8, 120.3.

Compound 2 was confirmed to be 3-(2-thiophene)-1,4,2-dioxazol-5-one. Theproduct was an off-white solid that decomposed rapidly above 192° C. andprovided a yield of 1.53 g, 76%, The ¹H NMR (CDCl₃, 500 MHz) spectrum isshown in FIG. 3 and indicates: δ=7.74 (dd, 1H, J=0.9 Hz, 3.8 Hz), 7.71(dd, 1H, J=0.9 Hz, 4.9 Hz), 7.23 (dd, 1H, J=3.9 Hz, 4.8 Hz). The ¹³C{¹H}NMR (CDCl₃, 75 MHz) is shown in FIG. 4 and indicates: δ=160.4, 153.6,133.0, 132.5, 128.7, 120.6.

Compound 3 was confirmed to be 3-(p-tolyl)-1,4,2-dioxazol-5-one. Theproduct was a a white solid with a melting point of 234-236° C. andprovided a yield of 1.63 g, 77%. The ¹H NMR (CDCl₃, 300 MHz) spectrum isshown in FIG. 5 and indicates: δ=7.74 (d, 2H, J=8.3 Hz), 7.35 (d, 2H,J=8.0 Hz), 2.45 (s, 3H). The ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum isshown in FIG. 6 and indicates: 163.9, 154.2, 145.0, 130.3, 126.8, 117.5,22.0.

Compound 4 was confirmed to be 3-(2-naphthyl)-1,4,2-dioxazol-5-one. Theproduct was a white solid with a melting point of 108-109° C. andprovided a yield of 2.15 g, 84%. The ¹H NMR (CDCl₃, 500 MHz) spectrum isshown in FIG. 7 and indicates: δ=8.37 (br. s, 1H), 7.98 (t, 2H, J=8.8Hz), 7.92 (d, 1H, J=8.1 Hz), 7.87 (dd, 1H, J=1.6 Hz, 8.5 Hz), 7.60-7.72(m, 2H). The ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum is shown FIG. 8 andindicates: δ=163.8, 154.0, 135.6, 132.5, 129.6, 129.3, 129.2, 128.4,128.2, 127.8, 121.5, 117.3.

Compound 5 was confirmed to be 3-(p-fluorophenyl)-1,4,2-dioxazol-5-one.The product was a white solid with a melting point of 66-68° C. andprovided a yield of 1.07 g, 49%. The ¹H NMR (CDCl₃, 300 MHz) spectrum isshown in FIG. 9 and indicates: δ=7.93-7.84 (m, 2H), 7.30-7.20 (m, 2H).The ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum is shown in FIG. 10 andindicates: δ=167.1, 165.1, 163.0, 153.9, 129.4 (d, J=9.3 Hz), 117.2 (d,J=23.1 Hz). The ¹⁹F NMR (CDCl₃, 282 MHz) spectrum is shown in FIG. 11and indicates: δ=−102.6 (m).

Compound 6 was confirmed to be 3-(m-fluorophenyl)-1,4,2-dioxazol-5-one.The product was a white solid with a melting point of 64-65° C. andprovided a yield of 1.11 g, 51%. The ¹H NMR (CDCl₃, 300 MHz) spectrum isshown in FIG. 12 and indicates: δ=7.67 (dt, 1H, J=1.3 Hz, 7.8 Hz),7.63-7.69 (m, 2H), 7.35 (t, 1H, J=7.6 Hz). The ¹³C{¹H} NMR (CDCl₃, 75MHz) spectrum is shown in FIG. 13 and indicates: δ=162.9 (d, J=248 Hz),162.8 (d, J=3.1 Hz), 153.5, 131.5 (d, J=8.1 Hz), 122.6 (d, J=3.0 Hz),122.4 (d, J=8.6 Hz), 121.1 (d, J=21.3 Hz), 113.8 (d, J=24.8 Hz). The ¹⁹FNMR (CDCl₃, 282 MHz) spectrum is shown in FIG. 14 and indicates:δ=-106.9 (m).

Compound 7 was confirmed to be 3-(o-fluorophenyl)-1,4,2-dioxazol-5-one.The product was a white solid with a melting point of 79-80° C. andprovided a yield of 1.53 g, 70%. The ¹H NMR (CDCl₃, 500 MHz) spectrum isshown in FIG. 15 and indicates: δ=7.79 (td, 1H, J=1.3 Hz, 7.9 Hz),7.50-7.59 (m, 2H), 7.35 (tdd, 1H, J=0.9 Hz, 2.6 Hz, 8.3 Hz). The ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum is shown in FIG. 16 and indicates:δ=161.0 (d, J=5.4 Hz), 160.5 (d, J=156 Hz), 153.5, 135.7 (d, J=8.7 Hz),129.1, 125.1 (d, J=3.5 Hz), 117.4 (d, J=19.8 Hz), 108.9 (d, J=11.5 Hz).The ¹⁹F NMR (CDCl₃, 470 MHz) spectrum is shown in FIG. 17 and indicates:δ=−105.9 (m).

Compound 8 was confirmed to be 3-(p-methoxy)-1,4,2-dioxazol-5-one. Theproduct was a white solid with a melting point of 152-153° C. andprovided a yield of 1.53 g, 63%. The ¹H NMR (CDCl₃, 500 MHz) spectrum isshown in FIG. 18 and indicates: δ=7.79 (d, 2H, J=8.7 Hz), 7.02 (d, 2H,J=8.7 Hz), 3.89 (s, 3H). The ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum isshown in FIG. 19 and indicates: 163.9, 163.4 154.1, 128.6, 114.9, 112.2,55.6.

Compound 9 was confirmed to be 3-(p-nitrophenyl)-1,4,2-dioxazol-5-one.The product was a yellow solid with a melting point of 160-162° C. andprovided a yield of 1.95 g, 78%. The ¹H NMR (CDCl₃, 300 MHz) spectrum isshown in FIG. 20 and indicates: δ=8.42 (dt, 2H, J=1.9 Hz, 8.9 Hz), 8.08(dt, 2H, J=1.9 Hz, 8.9 Hz). The ¹³C {¹H} NMR (CDCl₃, 125 MHz) spectrumis shown in FIG. 21 and indicates: δ=162.2, 153.2, 151.0, 128.1, 125.8,124.8

Compound 10 was confirmed to be 3-(m-nitrophenyl)-1,4,2-dioxazol-5-one.The product was a yellow solid with a melting point of 94-96° C. andprovided a yield of 1.44 g, 58%. The ¹H NMR (CDCl₃, 300 MHz) spectrum isshown in FIG. 22 and indicates: δ=8.73 (t, J=1.7 Hz), 8.46-8.53 (m, 1H),8.18-8.23 (m, 1H), 7.79 (t, 1H, J=7.9 Hz). The ¹³C{¹H} NMR (CDCl₃, 75MHz) spectrum is shown in FIG. 23 and indicates: δ=162.1, 153.1, 148.8,132.1, 131.1, 128.2, 122.0, 121.9.

Compound 11 was confirmed to be 3-(o-nitrophenyl)-1,4,2-dioxazol-5-one.The product was an orange solid with a melting point of 44-46° C. andprovided a yield of 0.58 g, 23%. The ¹H NMR (CDCl₃, 500 MHz) spectrum isshown in FIG. 24 and indicates: δ=8.27 (dd, 1H, J=1.9 Hz, 7.0 Hz),7.85-7.93 (m, 2H), 7.82 (dd, 1H, J=2.3 Hz, 6.7 Hz). The ¹³C{¹H} NMR(CDCl₃, 125 MHz) spectrum is shown in FIG. 25 and indicates: δ=162.4,153.4, 147.6, 134.6, 134.4, 132.1, 125.7, 115.7.

Compound 12 was confirmed to be 3,3′-(1,4-phenylene)bis-1,4,2-dioxazol-5-one. The product was a white solid that decomposedslowly above 180° C. that provided a yield of 2.77 g, 91%. The ¹H NMR(CDCl₃, 300 MHz) spectrum is shown in FIG. 37 and indicates: δ=8.06 (s,4H). The ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum is shown in FIG. 38 andindicates: δ=135.5, 127.3 (it is suspected the weak ¹³C intensities aredue to sample decomposition).

Compound 13 was confirmed to be 3-(p-chlorophenyl)-1,4,2-dioxazol-5-one.The product was a white solid that decomposed violently at 145° C. andprovided a yield of 1.07 g, 49%. The ¹H NMR (CDCl₃, 500 MHz) spectrum isshown at FIG. 28 and indicates: δ=7.80 (d, 2H, J=8.7 Hz), 7.54 (d, 2H,J=8.6 Hz). The ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum is shown at FIG. 29and indicates: δ=162.9, 153.5, 140.4, 131.4, 129.9, 129.3, 127.9, 118.6.

Compound 14 was confirmed to be 3-(m-chlorophenyl)-1,4,2-dioxazol-5-one.The product was an off-white solid with a melting point of 34-35° C. andprovided a yield of 1.57 g, 66%. The ¹H NMR (CDCl₃, 300 MHz) spectrum isshown at FIG. 30 and indicates: δ=7.85 (br. s, 1H), 7.75 (d, 1H, J=7.8Hz), 7.62 (d, 1H, J=8.45 Hz), 7.50 (t, 1H, J=7.8 Hz). The ¹³C{¹H} NMR(CDCl₃, 125 MHz) spectrum is shown at FIG. 31 and indicates: δ=162.6,153.5, 135.8, 134.0, 130.9, 126.7, 124.8, 121.9.

Compound 15 was confirmed to be 3-(o-chlorophenyl)-1,4,2-dioxazol-5-one.The product was an off-white solid with a melting point of 41-43° C. andprovided a yield of 1.57 g, 58%. The ¹H NMR (CDCl₃, 300 MHz) spectrum isshown at FIG. 32 and indicates: δ=7.78 (d, 1H, J=7.7 Hz), 7.52-7.63 (m,2H), 7.42-7.50 (m, 1H). The ¹³C{¹H} NMR (CDCl₃, 125 MHz) spectrum isshown at FIG. 33 and indicates: δ=162.5, 153.5, 134.3, 133.9, 131.8,130.7, 127.5, 119.6.

One-Pot Method—Large Scale

Hydroxylamine hydrochloride (168 mmol, 11.67 g, 1.1 eq), was dissolvedin N,N-dimethylformamide (100 mL) at room temperature in a 2000-mLthree-necked round-bottomed flask equipped with a magnetic stir bar.Triethylamine (168 mmol, 23.5 mL, 1.1 eq) was added in one portion. Thesolution was stirred for 5 minutes, then ethyl acetate (1100 mL) wasadded to the solution, and the reaction mixture was cooled to 0° C.

Benzoyl chloride (153 mmol, 17.8 mL, 1.0 eq) and triethylamine (23.5 mL,168 mmol, 1.1 eq) were placed into separate dropper funnels, and addeddropwise to the 2000 mL round bottomed flask over the course of 15minutes. The reaction was allowed to gradually warm up to roomtemperature.

After five hours, N,N′-carbonyldiimidazole (153 mmol, 24.80 g, 1.0 eq)was added to the round-bottomed flask in one portion, and the reactionwas allowed to proceed for another 30 minutes at room temperature. Thereaction was quenched with 200 mL of 2 M HCl_((aq)), extracted withethyl acetate (2×200 mL), and dried over anhydrous Na₂SO₄. The ethylacetate was evaporated under reduced pressure, and 10% aqueous NaHCO₃was added to the remaining liquid to give the product3-phenyl-1,4,2-dioxazol-5-one (20.3 g, 81%), which was collected bysuction filtration.

Attenuated Total Reflectance Fourier Transform Infrared (ATR-FTIR)Spectroscopy

Products from the testing scale experiment were characterized by Fouriertransform infrared spectroscopy (FTIR) using a Cary 630 FTIR (AgilentTechnologies) equipped with a germanium crystal attenuated totalreflectance (ATR) accessory, controlled by MicroLab PC software, andmeasured at 4 cm⁻¹ resolution. The results of the ATR-FTIR for3-phenyl-1,4,2-dioxazol-5-one is shown in FIG. 34.

X-Ray Data Collection, Reduction, Solution and Refinement

3-phenyl-1,4,2-dioxazol-5-one crystals, obtained in the above describedtesting scale experiment, were attached to the tip of a 150 μm MicroLoopwith paratone-N oil. Measurements were made on a Bruker APEXII CCDequipped diffractometer (30 mA, 50 KV) using monochromated Mo Kαradiation (λ=0.71073 Å) at 125 K. APEX3 software1 was used for theinitial orientation and unit cell were indexed using a least-squaresanalysis of a random set of reflections collected from three series of0.5° wide scans, 10 seconds per frame and 12 frames per series that werewell distributed in reciprocal space. For data collection, four ω-scanframe series were collected with 0.5° wide scans, 30 second frames and366 frames per series at varying φ angles (φ=0°, 90°, 180°,270°). Thecrystal to detector distance was set to 6 cm and a complete sphere ofdata was collected. Cell refinement and data reduction were performedwith the Bruker APEX3 software¹, which corrects for beam inhomogeneity,possible crystal decay, Lorentz and polarization effects. Dataprocessing and a multi-scan absorption correction was applied usingAPEX3 software package. The structure was solved using SHELXT and allnon-hydrogen atoms were refined anisotropically using SHELXL with theOLEX2 graphical user interface. Hydrogen atoms were placed in calculatedpositions using an appropriate riding model and coupled isotropictemperature factors. Figures were made using Ortep-3 for Windows. FIG.35 shows the molecular structure of 3-phenyl-1,4,2-dioxazol-5-one (1),determined by single crystal X-ray diffraction (H atoms added based on¹H and ¹³C NMR results). Additional data are shown in Tables 3-7.

TABLE 3 Crystal data and structure refinement for 3-phenyl-1,4,2-dioxazol-5-one (“PDO”) Empirical formula C8 H5 N O3 Formulaweight   163.13 Temperature 421.15 K Wavelength 0.71073 Å Crystal systemMonoclinic Space group P 1 21/n 1 Unit cell dimensions a = 8.0463(11) Åα = 90°. b = 5.4847(8) Å β = 93.785(2)°. c = 16.073(2) Å γ = 90°. Volume707.78(17) Å³ Z  4 Density (calculated) 1.531 Mg/m³ Absorptioncoefficient 0.120 mm⁻¹ F(000) 336 Crystal size 0.17 × 0.16 × 0.05 mm³Theta range for data collection 2.540 to 29.209°. Index ranges −10 <= h<= 10, −7 <= k <= 7, −21 <= l <= 21 Reflections collected 8513 Independent reflections 1825 [R(int) = 0.0215] Completeness to theta =25.242°   100.0% Absorption correction Semi-empirical from equivalentsMax. and min. transmission 0.7458 and 0.7062 Refinement methodFull-matrix least-squares on F² Data/restraints/parameters 1825/0/109Goodness-of-fit on F²     1.030 Final R indices [I > 2sigma(I)] R1 =0.0329, wR2 = 0.0796 R indices (all data) R1 = 0.0425, wR2 = 0.0862Extinction coefficient n/a Largest diff. peak and hole 0.255 and −0.218e · Å⁻³

TABLE 4 Atomic coordinates (×10⁴) and equivalent isotropic displacementparameters (Å² × 10³) for PDO. U(eq) is defined as one third of thetrace of the orthogonalized U^(ij) tensor. x y z U(eq) C(1) 4035(1)5753(2) 2698(1) 23(1) N(1) 4320(1) 8141(2) 3847(1) 25(1) O(1) 3273(1)4658(1) 3336(1) 21(1) C(2) 3510(1) 6197(2) 4003(1) 19(1) O(2) 4670(1)7894(2) 2986(1) 27(1) C(3) 2852(1) 5520(2) 4794(1) 18(1) O(3) 4122(1)4934(2) 2020(1) 32(1) C(4) 3109(1) 7085(2) 5478(1) 22(1) C(5) 2443(1)6490(2) 6224(1) 26(1) C(6) 1542(1) 4354(2) 6294(1) 25(1) C(7) 1311(1)2785(2) 5620(1) 22(1) C(8) 1965(1) 3353(2) 4866(1) 20(1)

TABLE 5 Bond lengths [Å] and angles [°] for PDO. C(1)—O(1) 1.3679(13)C(1)—O(2) 1.3496(14) C(1)—O(3) 1.1865(14) N(1)—C(2) 1.2825(14) N(1)—O(2)1.4372(12) O(1)—C(2) 1.3670(12) C(2)—C(3) 1.4582(15) C(3)—C(4)1.3991(15) C(3)—C(8) 1.3951(15) C(4)—H(4) 0.9300 C(4)—C(5) 1.3842(16)C(5)—H(5) 0.9300 C(5)—C(6) 1.3862(17) C(6)—H(6) 0.9300 C(6)—C(7)1.3874(16) C(7)—H(7) 0.9300 C(7)—C(8) 1.3872(15) C(8)—H(8) 0.9300 O()—C(1)—O(1) 107.68(9) O(3)—C(1)—O(1) 125.43(11) O(3)—C(1)—O(2)126.89(11) C(2)—N(1)—O(2) 104.08(9) C(2)—O(1)—C(1) 105.63(9)N(1)—C(2)—O(1) 114.05(9) N(1)—C(2)—C(3) 126.87(10 O(1)—C(2)—C(3)119.08(9) C(1)—O(2)—N(1) 108.54(8) C(4)—C(3)—C(2) 119.05(10)C(8)—C(3)—C(2) 120.45(9) C(8)—C(3)—C(4) 120.49(10) C(3)—C(4)—H(4) 120.3C(5)—C(4)—C(3) 119.34(11) C(5)—C(4)—H(4) 120.3 C(4)—C(5)—H(5) 119.8C(4)—C(5)—C(6) 120.32(11) C(6)—C(5)—H(5) 119.8 C(5)—C(6)—H(6) 119.9C(5)—C(6)—C(7) 120.25(11) C(7)—C(6)—H(6) 119.9 C(6)—C(7)—H(7) 119.9C(8)—C(7)—C(6) 120.29(10) C(8)—C(7)—H(7) 119.9 C(3)—C(8)—H(8) 120.4C(7)—C(8)—C(3) 119.29(10) C(7)—C(8)—H(8) 120.4 Symmetry transformationsused to generate equivalent atoms:

TABLE 6 Anisotropic displacement parameters (Å² × 10³) for PDO. Theanisotropic displacement factor exponent takes the form: −2π²[h²a*²U¹¹ + . . . + 2 h k a* b* U¹²] U¹¹ U²² U³³ U²³ U¹³ U¹² C(1) 20(1)26(1) 22(1)  3(1) 1(1) 3(1) N(1) 27(1) 26(1) 20(1)  2(1) 0(1) −4(1) O(1) 24(1) 22(1) 18(1) −1(1) 2(1) −1(1)  C(2) 17(1) 19(1) 19(1) −1(1)−2(1)  2(1) O(2) 28(1) 30(1) 23(1)  4(1) 2(1) −5(1)  C(3) 16(1) 18(1)19(1)  0(1) −1(1)  4(1) O(3) 35(1) 38(1) 22(1) −1(1) 6(1) 5(1) C(4)21(1) 20(1) 24(1) −2(1) −1(1)  2(1) C(5) 27(1) 28(1) 21(1) −5(1) −2(1) 6(1) C(6) 24(1) 30(1) 20(1)  3(1) 3(1) 7(1) C(7) 21(1) 21(1) 26(1)  3(1)2(1) 2(1) C(8) 20(1) 19(1) 20(1) −1(1) −1(1)  2(1)

TABLE 7 Hydrogen coordinates (×10⁴) and isotropic displacementparameters (Å² × 10³) for PDO. x y z U(eq) H(4) 3722 8511 5432 26 H(5)2600 7529 6680 31 H(6) 1092 3970 6796 30 H(7) 715 1347 5672 27 H(8) 18142299 4414 23

Mass Spectrometry

Mass Spectrometry was then performed on the resulting PDO product of thetesting scale scale experiment, which had an exact mass of 163.027 u.The resulting mass spectrum is shown in FIG. 36. The data was collectedwith a CEC 21-110B Mass Spectrometer operated at low resolution(m/z=10-800, M/ΔM=2500) in positive ion mode using soft EI ionization.PDO and related compounds showed very poor or no signal intensity,preventing collecting of high resolution spectrum. The main peak at198.1 amu is thought to be an impurity produced byoxidation/decomposition of the PDO molecule (for example, this peak maycorrespond to C₈H₈O₅N⁺ (m/z=198.04 amu) or a similar compound).

As described herein, provided is a simple one-pot method for thesynthesis of 3-aryl-substituted-1,4,2-dioxazol-5-ones. The reactionconditions are mild and can easily be performed in a single day withminimal energy requirements. Moreover, the methods described herein donot require the use of toxic halogenated solvents. AlthoughN,N-dimethylformamide is also considered a harmful solvent, the presentmethods primarily use ethyl acetate, which is a relatively benignsolvent. Therefore only a very small amount of N,N-dimethylformamide isneeded, relative to the quantity of dichloromethane required forexisting procedures. In addition, the reaction is robust, shown hereintolerate a wide variety of substituents on the aromatic ring. Theprecursor materials are significantly more available from commercialsuppliers than previously known methods. Finally, the reaction isdemonstrably easy to scale up, making it a potentially suitable routefor industrial scale production of 3-aryl-1,4,2-dioxazol-5-onecompounds. It is noted that some benzoic acid impurities were present inthe product, but these were readily removed by washing with aqueousNa₂CO₃ solution. In certain embodiments described herein, the productshould not be washed with stronger bases, such as NaOH, which couldcause the product to hydrolyze.

The foregoing disclosure is not intended to limit the present disclosureto the precise forms or particular fields of use disclosed. As such, itis contemplated that various alternative embodiments and/ormodifications to the present disclosure, whether explicitly described orimplied herein, are possible in light of the disclosure. Having thusdescribed embodiments of the present disclosure, a person of ordinaryskill in the art will recognize that changes may be made in form anddetail without departing from the scope of the present disclosure. Thus,the present disclosure is limited only by the claims. Reference toadditives in the specification are generally to operative additivesunless otherwise noted in the specification.

In the foregoing specification, the disclosure has been described withreference to specific embodiments. However, as one skilled in the artwill appreciate, various embodiments disclosed herein can be modified orotherwise implemented in various other ways without departing from thespirit and scope of the disclosure. Accordingly, this description is tobe considered as illustrative and is for the purpose of teaching thoseskilled in the art the manner of making and using various embodiments ofthe disclosed chemical system. It is to be understood that the forms ofdisclosure herein shown and described are to be taken as representativeembodiments. Equivalent elements, or materials may be substituted forthose representatively illustrated and described herein. Moreover,certain features of the disclosure may be utilized independently of theuse of other features, all as would be apparent to one skilled in theart after having the benefit of this description of the disclosure.Expressions such as “including”, “comprising”, “incorporating”,“consisting of”, “have”, “is” used to describe and claim the presentdisclosure are intended to be construed in a non-exclusive manner,namely allowing for items, components or elements not explicitlydescribed also to be present. Reference to the singular is also to beconstrued to relate to the plural. Reference to “about” or“approximately” is to be construed to mean plus or minus 10%.

Further, various embodiments disclosed herein are to be taken in theillustrative and explanatory sense, and should in no way be construed aslimiting of the present disclosure. All joinder references (e.g.,attached, affixed, coupled, connected, and the like) are only used toaid the reader's understanding of the present disclosure, and may notcreate limitations, particularly as to the position, orientation, or useof the systems and/or methods disclosed herein. Therefore, joinderreferences, if any, are to be construed broadly. Moreover, such joinderreferences do not necessarily infer that two elements are directlyconnected to each other.

Additionally, all numerical terms, such as, but not limited to, “first”,“second”, “third”, “primary”, “secondary”, “main” or any other ordinaryand/or numerical terms, should also be taken only as identifiers, toassist the reader's understanding of the various elements, embodiments,variations and/or modifications of the present disclosure, and may notcreate any limitations, particularly as to the order, or preference, ofany element, embodiment, variation and/or modification relative to, orover, another element, embodiment, variation and/or modification.

It will also be appreciated that one or more of the elements depicted inthe drawings/figures can also be implemented in a more separated orintegrated manner, or even removed or rendered as inoperable in certaincases, as is useful in accordance with a particular application.

1. A method of preparing a 3-R-1,4,2-dioxazol-5-one compound,comprising: combining hydroxylamine, or a salt thereof, and a firstorganic solvent to form a first reaction mixture; adding anR-substituted acyl halide to the first reaction mixture to form a secondreaction mixture; adding N,N′-carbonyldiimidazole to the second reactionmixture to form a third reaction mixture; and obtaining a3-R-1,4,2-dioxazol-5-one compound from the third reaction mixture,wherein the first, second and third reaction mixtures are formed by aone-pot method.
 2. The method of claim 23, wherein the R-substitutedacyl chloride is selected from the group consisting of benzoyl chloride,2-thiophenecarbonyl chloride, p-toluoyl chloride, 2-naphthoyl chloride,p-fluorobenzoyl chloride, m-fluorobenzoyl chloride, o-fluorobenzoylchloride, p-methoxybenzoyl chloride, p-nitrobenzoyl chloride,m-nitrobenzoyl chloride, o-nitrobenzoyl chloride, p-teraphthaloylchloride, p-chlorobenzoyl chloride, m-chlorobenzoyl chloride,o-chlorobenzoyl chloride, and combinations thereof.
 3. The method ofclaim 1, wherein the first organic solvent is selected from the groupconsisting of N,N-dimethylformamide (DMF), ethyl acetate, andcombinations thereof.
 4. The method of claim 1, further comprisingdissolving the R-substituted acyl halide in a second organic solventprior to adding the R-substituted acyl halide to the second reactionmixture.
 5. The method of claim 4, wherein the second organic solvent isselected from the group consisting of ethyl acetate, tetrahydrofuran,and combinations thereof.
 6. The method of claim 27, wherein the thirdorganic solvent is selected from the group consisting of ethyl acetate,tetrahydrofuran, and combinations thereof.
 7. (canceled)
 8. (canceled)9. (canceled)
 10. (canceled)
 11. The method of claim 1, wherein the3-R-1,4,2-dioxazol-5-one compound is obtained at a purity of at least 50wt. %.
 12. The method of claim 1, further comprising purifying the3-R-1,4,2-dioxazol-5-one compound to a purity of at least 75 wt. %. 13.The method of claim 12, further comprising purifying the3-R-1,4,2-dioxazol-5-one compound to a purity of at least 90 wt. %. 14.The method of claim 1, wherein the method is performed at ambienttemperature and pressure.
 15. The method of claim 1, wherein the firstreaction mixture is cooled to 0° C.
 16. The method of claim 1, whereinthe 3-R-1,4,2-dioxazol-5-one compound is selected from the groupconsisting of 3-phenyl-1,4,2-dioxazol-5-one,3-thiophene-1,4,2-dioxazol-5-one, 3-tolyl-1,4,2-dioxazol-5-one,3-(2-naphthyl)-1,4,2-dioxazol-5-one,3-(p-fluorophenyl)-1,4,2-dioxazol-5-one,3-(m-fluorophenyl)-1,4,2-dioxazol-5-one,3-(o-fluorophenyl)-1,4,2-dioxazol-5-one,3-(p-methoxyphenyl)-1,4,2-dioxazol-5-one,3-(p-nitrophenyl)-1,4,2-dioxazol-5-one,3-(m-nitrophenyl)-1,4,2-dioxazol-5-one,3-(o-nitrophenyl)-1,4,2-dioxazol-5-one,3,3′-(1,4-phenylene)-bis-1,4,2-dioxazol-5-one,3-(p-chlorophenyl)-1,4,2-dioxazol-5-one,3-(m-chlorophenyl)-1,4,2-dioxazol-5-one,3-(o-chlorophenyl)-1,4,2-dioxazol-5-one, and combinations thereof.
 17. A3-R-1,4,2-dioxazol-5-one compound prepared by the method of claim
 1. 18.The compound of claim 17, wherein the compound is selected from thegroup consisting of 3-phenyl-1,4,2-dioxazol-5-one,3-thiophene-1,4,2-dioxazol-5-one, 3-tolyl-1,4,2-dioxazol-5-one,3-(2-naphthyl)-1,4,2-dioxazol-5-one,3-(p-fluorophenyl)-1,4,2-dioxazol-5-one,3-(m-fluorophenyl)-1,4,2-dioxazol-5-one,3-(o-fluorophenyl)-1,4,2-dioxazol-5-one,3-(p-methoxyphenyl)-1,4,2-dioxazol-5-one,3-(p-nitrophenyl)-1,4,2-dioxazol-5-one,3-(m-nitrophenyl)-1,4,2-dioxazol-5-one,3-(o-nitrophenyl)-1,4,2-dioxazol-5-one,3,3′-(1,4-phenylene)-bis-1,4,2-dioxazol-5-one,3-(p-chlorophenyl)-1,4,2-dioxazol-5-one,3-(m-chlorophenyl)-1,4,2-dioxazol-5-one,3-(o-chlorophenyl)-1,4,2-dioxazol-5-one, and combinations thereof. 19.The compound of claim 18, wherein the 3-R-1,4,2-dioxazol-5-one compoundis 3-methyl-1,4,2-dioxazol-5-one.
 20. The compound of claim 18, whereinthe 3-R-1,4,2-dioxazol-5-one compound is 3-phenyl-1,4,2-dixoazol-5-one.21. The compound of claim 18, wherein the 3-R-1,4,2-dioxazol-5-onecompound has a purity of at least 50 wt. %.
 22. The method of claim 1,wherein the hydroxylamine is hydroxylamine hydrochloride.
 23. The methodof claim 1, wherein the R-substituted acyl halide is an R-substitutedacyl chloride.
 24. The method of claim 1, further comprising adding anamine compound to the first reaction mixture.
 25. The method of claim24, wherein the amine compound is triethylamine.
 26. The method of claim1, further comprising adding an additional amine compound to the secondreaction mixture.
 27. The method of claim 26, further comprisingdissolving the additional amine compound in a third organic solventprior to adding the additional amine compound to the second reactionmixture.
 28. The method of claim 1, further comprising adding an acid tothe third reaction mixture prior to obtaining the3-R-1,4,2-dioxazol-5-one compound.
 29. A method of preparing a3-R-1,4,2-dioxazol-5-one compound, comprising: combining hydroxylaminehydrochloride, triethylamine, N,N-dimethylformamide (DMF) and ethylacetate to form a first reaction mixture, wherein the first reactionmixture is cooled to 0° C.; adding an R-substituted acyl chloride andadditional triethylamine to the first reaction mixture to form a secondreaction mixture, wherein the second reaction mixture is warmed to roomtemperature; adding N,N′-carbonyldiimidazole to the second reactionmixture to form a third reaction mixture; adding an acid to the thirdreaction mixture to form a quenched reaction mixture; and obtaining a3-R-1,4,2-dioxazol-5-one compound from the quenched reaction mixture,wherein the first, second, third and quenched reaction mixtures areformed by a one-pot method.